We have examined whether ventral forebrain dopamine projection areas were activated prior to motor behavior, during anticipation of reward and punishment, as opposed to during responses following reward and punishment. During the approach interval, subjects saw a cue indicating that they could either win money or not, waited a variable delay, and then pressed a button in response presentation of a target. If subjects responded before the target following the reward cue disappeared, they won $5.00, $1.00, or $.20 whereas their response to the neutral target did not affect their total. During the active avoidance task, subjects were given $20.00 and responded to targets that followed either a punishment cue or a neutral cue. If they failed to respond before the disappearance of the target following the punishment cue, they lost $5.00, $1.00, or $.20 whereas their response to the neutral target again did not affect their total. T2*-weighted gradient echoplanar MR volumes depicting blood oxygenation level dependent (BOLD)-contrast were acquired using a 1.5 or 3.0 Tesla GE System. After correcting for in-plane motion, individual voxel activations were correlated with an ideal waveform corresponding to the expected activation time course using the AFNI software package. The ideal waveform consisted of a waveform representing the task which was convoluted with the brain hemodynamic response function. Anticipation of reward activated striatal areas (caudate, putamen) and mesial forebrain areas (anterior cingulate, mesial prefrontal cortex, and thalamic regions). Anticipation of punishment also activated these regions relative to anticipation of no monetary outcome. However, anticipation of reward but not punishment produced activation in the nucleus accumbens. Magnitude of nucleus accumbens activation predicted the amount of positive emotion subjects reported feeling when the cues signaling monetary reward. We also separately examined reward anticipation and outcomes with event-related fMRI. This study confirmed that the nucleus accumbens was primarily recruited by anticipation of monetary reward. [unreadable] [unreadable] Studies are currently ongoing to compare the brain response to anticipation of working to gain reward or to avoid punishment in adolescents with and without a family history of alcoholism or substance abuse. These studies have shown that healthy adolescents without a family history of alcoholism activate the same brain circuit during anticipation of working for reward as adults do, but that the magnitude of the activation is less than the magnitude seen in adults. In addition, we have also begun comparing brain motivation circuits in alcoholics and controls. Initial results from this work suggest that alcoholics studied three weeks from their last drink also shown a blunted response in the nucleus accumbens during the anticipation of working for reward as well as during the notification of successful outcome. [unreadable] [unreadable] We have also developed a series of fMRI tasks which allow us to examine brain BOLD response during a risk taking task in which financial reward is determined by how much risk an individual is willing to endure. This task shows robust BOLD activation in the cognitive division of the anterior cingulate cortex, and that this activation is less pronounced among adolescents. This may represent a brain correlate of the developmental tendency of adolescents to engage in risky behavior. [unreadable] [unreadable] Studies are also underway to examine the relationship between the magnitude of voluntary effort required to complete a task, uncertainity of reward and the magnitude of BOLD activation in the ventral striatum. During fMRI, subjects saw cues signaling probabilities of 1.0, 0.5, and 0 of winning $1 for hitting a subsequent target, and cues signaling similar probabilities of reward delivery requiring no instrumental response. Non-instrumental reward anticipation did not elicit activation. Instrumental reward anticipation activated multiple nodes of the basal ganglia-thalamocortical motor circuit. Ventro-mesial striatum was activated by joint requirement for an instrumental response together with uncertain (but not certain) reward.[unreadable] [unreadable] Using the an advanced version of the motivational task described above which allows us to more clearly separate individual events during a sequence of motivated behavior, we have recently shown that alcoholics are more sensitive to the notification of both rewarding or punishing outcomes than non-alcoholic controls. This increased sensitivity to outcome is present in both the ventral striatum and the anterior insular cortex and may relate to differences in impulsivity that characterize substance abusing individuals. [unreadable] [unreadable] The effect of pharmacological probes such as amphetamine, dopamine depletion and intravenously administered ethanol are also being investigated. Preliminary evidence suggests that intravenously administered ethanol is associated with an decrease in BOLD signal in the ventral forebrain, including extended amygdala and ventral striatum.[unreadable] [unreadable] We have also used an event-related fMRI approach to examine alcoholics brain blood oxygenation level dependent (BOLD) response during their evaluation of emotional stimuli and to compare their response to that of non-alcoholic controls. The task used was a simplified variant of a facial emotion-decoding task in which subjects determined the intensity level of a target emotion displayed as a facial expression. Facial expressions of happy, sad, anger, disgust and fear were used as stimuli. Alcoholics and controls did not differ in the accuracy with which they identified the intensity level during the simple emotional decoding task but there were significant differences in their BOLD response during evaluation of facial emotion. In general, alcoholics showed less brain activation than non-alcoholic controls. The greatest differences in activation were during decoding of facial expressions of fear and disgust during which alcoholics had significantly less activation than controls in the affective division of the anterior cingulate cortex (ACC). Alcoholics also had significantly less activation than controls in the affective division of the ACC while viewing sad faces. Only to facial expressions of anger did the alcoholics show any significant activation in the affective ACC and in this case their BOLD response did not significantly differ from that of the controls. These results suggest that alcoholics show a deficit in the function of the affective division of the ACC during evaluation of negative facial emotions that can serve as cues for flight or avoidance. This deficit may underlie some of the behavioral dysfunction in alcoholism.